Delivery of drugs to the central nervous system (CNS) remains a challenge, despite recent advances in drug delivery and knowledge of mechanisms of delivery of drugs to the brain. For example, CNS targets are poorly accessible from the peripheral circulation due to the blood-brain barrier (BBB), which provides an efficient barrier for the diffusion of most, especially polar, drugs into the brain from the circulating blood. Attempts to circumvent the problems associated with the BBB to deliver drugs to the CNS include: 1) design of lipophilic molecules, as lipid soluble drugs with a molecular weight of less than 600 Da readily diffuse through the barrier; 2) binding of drugs to transporter molecules which cross the BBB via a saturable transporter system, such as transferrin, insulin, IGF-1, and leptin; and 3) binding of drugs to polycationic molecules such as positively-charged proteins that preferentially bind to the negatively-charged endothelial surface (See, e.g., Illum, Eur. J. Pharm. Sci. 11:1-18 (2000) and references therein; W. M. Partridge. “Blood-brain barrier drug targeting: the future of brain drug development”, Mol Interv. 3(2):90-105 (2003); W. M. Partridge et al., “Drug and gene targeting to the Brain with molecular Trojan horses”, Nature Reviews-Drug Discovery 1:131-139 (2002)).
The intranasal route has been explored as a non-invasive method to circumvent the BBB for transport of drugs to the CNS. Although intranasal delivery to the CNS has been demonstrated for a number of small molecules and some peptides and smaller proteins, there is little evidence demonstrating the delivery of protein macromolecules to the CNS via intranasal pathways, presumably due to the larger size and varying physico-chemical properties unique to each macromolecule or class of macromolecules, that may hinder direct nose-to-brain delivery.
The primary physical barrier for intranasal delivery is the respiratory and olfactory epithelia of the nose. It has been shown that the permeability of the epithelial tight junctions in the body is variable and is typically limited to molecules with a hydrodynamic radius less than 3.6 A; permeability is thought to be negligible for globular molecules with a radius larger than 15 A (B. R. Stevenson et al., Mol. Cell. Biochem. 83, 129-145(1988)). Therefore, the size of the molecule to be administered is considered an important factor in achieving intranasal transport of a macromolecule to the central nervous system. Fluorescein-labeled dextran, a linear molecule having a dextran molecular weight of 20 kD can be delivered to cerebrospinal fluid from the rat nasal cavity, however 40 kDa dextran cannot (Sakane et al, J. Pharm. Pharmacol. 47, 379-381 (1995)). It has also been reported that an infectious organism, such as a virus, can enter the brain through the olfactory region of the nose (S. Perlman et al., Adv. Exp. Med. Biol., 380:73-78 (1995)).
In published delivery studies to date, intranasal delivery efficiency to the CNS has been very low and the delivery of large globular macromolecules, such as antibodies and their fragments, has not been demonstrated. Yet, because antibodies, antibody fragments, and antibody fusion molecules are potentially useful therapies for treating disorders having a CNS target, e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, epilepsy, and metabolic and endocrine disorders, it is desirable to provide a method for delivering these large macromolecules to the CNS non-invasively.